Cannabis is the most used illicit substance in the United States. Previous studies suggest that atypical antipsychotics decrease the frequency and the amount of substance use in subjects with and without psychotic illness. So far, there are no controlled studies assessing the effectiveness of atypical antipsychotics for decreasing cannabis and other substance use in individuals with cannabis use disorders. We postulate that the atypical antipsychotic quetiapine is an effective agent for improving substance use outcomes in subjects with cannabis use disorders. In this pilot study, we will test this hypothesis in heavy cannabis users (i.e., individuals who are cannabis dependent and smoke three times or more per week). Because 50% of these heavy cannabis users report histories of psychotic experiences (i.e., attenuated positive symptoms) while smoking and are at risk for recurring psychotic symptoms, we will focus this pilot clinical trial on this subgroup of cannabis users in order to increase the risk/benefit ratio of this study and target a population that may also benefit from the antipsychotic effect of quetiapine. Considering the lack of controlled studies assessing the efficacy of atypical antipsychotics in heavy cannabis users, assessing the effectiveness of an atypical antipsychotic medication on substance use and clinical outcomes in this population is critical for improving the prognosis of these individuals. Thus, the aims of this randomized, double-blind, placebo-controlled study are to assess the efficacy of an atypical antipsychotic (quetiapine) in 120 subjects with cannabis dependence, a recent history (within a year) of attenuated psychotic symptoms, and using cannabis 3 times or more per week for: (1) decreasing the use of cannabis and other substances;and (2) preventing the recurrence of psychotic experiences. We will also assess the effects of quetiapine on craving and mood, and its tolerability. This project will be a 12-week, randomized, double-blind, placebo-controlled study with quetiapine and it will include a comprehensive assessment of symptoms, substance use, and side effects. This study will benefit the field by providing unique data on the relative efficacy and tolerability of treatment with atypical antipsychotics in heavy cannabis users with a vulnerability to psychosis. This study will be the basis for future studies assessing the long-term efficacy and tolerability of atypical antipsychotics in individuals with cannabis use disorders. PUBLIC HEALTH RELEVANCE: Cannabis is the most used illicit substance in the United States, and there are no recommended pharmacological intervention for decreasing substance use and improving clinical outcomes in subjects with cannabis dependence. Thus, this study could have high public health relevance if it demonstrates the efficacy of an atypical antipsychotic for improving the prognosis of these individuals.